ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.137G>T (p.Arg46Leu) (rs772551056)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473045 SCV000554015 likely pathogenic Paragangliomas 4 2017-06-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 46 of the SDHB protein (p.Arg46Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with pheochromocytoma and paraganglioma (PHEO-PGL) syndrome (PMID: 23175444). ClinVar contains an entry for this variant (Variation ID: 412478). Experimental studies have shown that the p.Arg46Leu missense variant severely disrupts protein function in a yeast complementation assay (PMID: 23175444). Two different missense substitution at this codon (p.Arg46Gly, p.Arg46Gln) have been determined to be pathogenic (PMID: 14500403, 15328326, 25972245). This suggests that the arginine residue is critical for SDHB protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that involves a critically important residue and has been shown to be deleterious in a model organism. It is also absent from the general population and reported in a single affected individual. For these reasons, and in the absence of additional genetic and/or functional evidence, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000571526 SCV000664561 likely pathogenic Hereditary cancer-predisposing syndrome 2017-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species

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